The final goal of this study is to develop new strategies to rapidly reduce tumor burden while synergize with the tumor-specific immune response to eradicate the tumor. Most current chemotherapies transiently reduce tumor burden but concomitantly inhibit immune responses while current immunotherapeutic strategies alone fail to clear established tumors. The microenvironment of established tumors often prevents effective T cell priming or inhibits the effector phase of activated T cells entering tumor tissues for tumor destruction. To develop novel approaches for strong anti-tumor immunity without defined tumor antigens, we directly targeted tumor tissues with LIGHT, TNF superfamily member 14 (TNFSF14), which acts to break the tumor barrier by recruiting more immune cells directly to the tumor site and enhancing anti-tumor immunity against metastasis. Targeting tumors with anti-Her2 can greatly reduce tumor burden but fails to eradicate tumors alone. To test the potential efficacy of the combined treatments using ad-LIGHT and anti-her2/neu antibody to treat a neu+ tumor, we observed a remarkable synergy between LIGHT and anti-Her2/neu in effectively controlling primary tumor growth. We hypothesize that specific targeting of tumors with LIGHT enhances anti-her2/neu mediated apoptosis of tumor cells and amplifies LIGHT-mediated immunity against a Her2* tumor. Specifically, anti-her/neu might induce more apoptosis to break the tumor barrier and lead to better priming of T cells while ad-LIGHT expressed inside the tumor will lead to enhanced recruitment of additional FcR+ cells to enhance the apoptotic effect and further amplify the recruitment of activated T cells into tumor sites. Aim 1 will study whether, and how, LIGHT can synergize with anti- Her2/neu to reject an established tumor. We will determine whether the synergy is immune mediated. If active immunity is enhanced, we will determine which types of immune cells are involved to overcome tumor suppression at the priming and effector phases. We will also determine whether combined treatment is able to generate strong immunity against not only neu+ tumors but also other tumor antigens to eradicate metastasis. Aim 2 will explore whether linking anti-neu with LIGHT can systemically target micrometastasis. Our preliminary data suggest that a fusion protein linking an antibody specific for a tumor antigen and LIGHT can effectively inhibit tumor growth. We propose that using single chain of anti-neu with LIGHT might localize LIGHT to distal tumor sites thereby facilitating immune cell targeting to micrometastases. Aim 3 will explore whether ad-LIGHT-neu-HA can be used as a therapeutic vaccine. We propose that ad-LIGHT-neu can serve as a new therapeutic vaccine, since it provides first and second signaling as well as innate signaling, especially for micrometastasis. Our study may provide new strategies to treat various patients by combining conventional treatment and a novel immunotherapy.